8-aza-(linear naphthothiazole)-4, 9-quinones substituted in the 2-position



United States Patent C) 3,005,824 S-AZA (LWEAR NAPHTHOTHIAZOLE) 4,9- QUI- NONES SUBSTITUTED IN THE 2-POSITION Gerhard Domaglr, Wuppertal=Elberfeld, Karl-Wolfgang 3chellhammer and Siegfried Petersen, Leverkusen, and Hans-Bode Ktinig, Wuppertal=Elberfeld, Germany, assignors to Farbenfabriken Bayer Aktiengesellschaft, Leverirusen, Germany, a corporation of Germany No Drawing. Filed Mar. 27, 1959, Ser. No. 802,292 Claims priority, application Germany Mar. 29, 1958 '7 tliaims. (Cl. 260-288) This invention relates to certain novel compositions of matter useful in chemotherapy and, more particularly, it is concerned with certain novel compositions that are useful in the treatment of various forms ofv rheumatoid arthritis.

It is known that the term rheumatoid arthritis embraces many forms of disease condition. However, certain of these forms, notably, acute rheumatism or chronic infectious arthritis, are generally recognized as being infectious diseases having an anatomic substrate characteristic of such diseases. It has been observed that many rheumatics have a previous history of sub-acute bacterial endocarditis, diseases that commonly are associated with the presence of streptococci, viridans streptococci and enterococci, frequently found in symbiosis with actinomycetic pathogens. For example, it has been observed that in the tonsils of rheumatic patients Actinomycetes have been discovered in symbiosis with streptococci. It has also been observed. that nodularrheumatoid arthritis generally presents disease symptoms inwhich the anatomical changes resemble much more closely an actinomycetic infection than a purely streptococcal infection.

There are known today many chemotherapeutic sub-' stances that arehighly efiective against streptococci, notably 2-(p-aminobenzenesulfonamide)-pyrimidine (Sulfa diazine) and the combination of Z-(p-aminobenzenesulfonamide)-4-methylpyrimidine with the 4-aminobenzenesulfothiocarbamide salt of 4-aminoethylbenzenesulfonamide. However, it has been found that sulfonamides have an unsatisfactory therapeutic effect and only a slight prophylactic effect on rheumatoid arthritis. It has been found further that the effectiveness of these highly active sulfonamides upon streptococci is materially reduced in the presence of Actinomycetes. In accordance with the present invention, it is found that rheumatoid arthritis due to infectious causes canv be controlled or prevented most successfully by the conjunctive use of sul-- fonamides with substances that are highly active against Actinomycetes.

It is known that linear naphthoxazoleor naphthothiazole-4,9-quinones which are alkylated in the 2-position jare valuable therapeutically (U.S. patent application Serial No. 729,566) and it is. now found, remarkably, as a result of further studies in this field, that certain S-aza analogs of these compounds likewise possess chemotherapeutic activity. More particularly, it is found that these compounds have bacteriostatic activity against Actinomycetes and, especially important, against tubercle bacilli.

In accordance with the process aspects of this invention, 6-amino-7-ha1o,7-hydroxy', or 7-mercapto-5,8-quinolinequinones are reacted with aldehydes or carboxylic acid derivatives to yield linear 8-aza-naphthoxazoleor 8 -aza-naphthothiazole-4,9-quinones, substituted in the 2- position. The starting materials required for preparation of the new compounds have been described in copending United States patent application Serial No. 802,- 290-, filed concurrently with this case.

These new compounds are prepared by first creating a carbon-nitrogen link between the nitrogen atom in the 6 position of the quinolinequinone and a carboxylic acid derivative or an aldehyde by acylation or condensation to a Schilfs base. The N-acyl compounds are then cyclized by heating, water being split off in the case of quinolinequinones substituted in position 7 by an hydroxyl or mercapto group, and hydrogen halide being split off in the case of quinolinequinones substituted in position 7 by a halogen atom, to form axazoles or thiazoles.

The first stage in the preparation of the new products utilizing carboxylic acid derivatives is the acylation of the nitrogen atom in the 6-position. Therefore, derivatives of 5,8-quinolinequinones that are acylated on thisnitrogen atom may also serve as initial reactants.

8-aza-(linear naphthoxazole)-4,9-quinones which may be substituted in the nitrogen-containing nucleus and in the 2-position are obtained if 6-amino-7-haloor 6- amino-7-hydroxy-5,S-quinolinequinones are heated with derivatives of carboxylic acids such as acid anhydrides or acid chlorides in inert solvents or in an excess of the acylating agent to temperatures above 100 C. Examples of suitable inert solvents are xylene, the chloroben zenes, nitrobenzene, or decahydronaphthalene. If 6-acylamino-7-haloor -hydroXy-5,8-quinolinequinones are em-' ployed, heating in inert solvents is suficient to bring about the. cyclization.

The preparation of 8-aza-(linear naphthothiazole)-4,9- quinones substituted in 2-position and possibly substituted in the nitrogen-containing nucleus as indicated above may be accomplished by the process described in German Patent 485,322., The aforementioned 6-amino-7-halo- 5,8-quinolinequinones are reacted in water or aqueous ethanol with salts of hydrogen sulfide, and the resultant 6'-amino-7-mercapto-5,8-quinolinequinones are condensed with aldehydes such as benzaldehyde. The first stage of the reaction presumably involves formation of a Schilfs base. The hydrogen atom of the mercapto group in position 7 adds to the carbon-nitrogen double bond to form a heterocycle, and this is subsequently oxidized further by atmospheric oxygen to give the thiazole.

The compounds according to this invention and prepared according to this process are yellow to orange-- colored crystalline substances which are moderately soluble in water and organic solvents. They are effective against human tubercle bacilli, particularly against those which are resistant to other tuberculostatic agents such as PAS, isoniazid or streptomycin. The compounds containingthe. thiazole ring prevent the growth of actinomyces in dilutions of 1:200,000. The compound 2-furyl-8-aza- (linear naphthiazol)-4,9-quinone is an effective bacteriosxtatic agent and inhibits the growth both of normal and resistant tubercle bacilli in dilutions of 1:500,000. The heterocyclically anellated quinones are also eflective when they are reduced and the resultant hydroquinones stabilized by acylation.

The compounds according to this invention are represented by the following formula:

Rr-l

a sulfonamide selected from the group consisting of 2-' (p-aminobenzenesulfonamide)-pyrimidine combined with the 4-aminobenzenesulfothiocarbamide salt of 4-aminoethylbenzenesulfonamide. An analgesic such as aspirin may advantageously be included in the combination but the first mentioned substances perform synergistically to effect the desired relief of the symptoms of chronic infectious rheumatoid arthritis. The novel compositions of matter according to this invention may be produced in the form of capsules, emulsions, solutions or the like as is well known in the pharmaceutical arts. While the proportion of the synergistically active components may be substantially altered without departure from the spirit of this invention, it is preferred that the sulfonamide be present in the mixture in an amount approximating ten times the amount by weight of the other synergistically active component.

In order to facilitate a better understanding of the subject matter of this invention, specific examples hereafter follow in which the preparation of several of the compositions is described. It will be understood, however, that these examples are provided by way of illustration merely and are not to be regarded as imposing any limitations upon the invention except as the same is defined in the subjoined claims.

Example I About 25 grams of 6-arnino-7-chloro-5,8-quinolinequinone is heated to the boil for 1 hour in 200 cubic centimeters of acetic anhydride in the presence of 1 cubic centimeter of concentrated sulfuric acid. On the following day dark crystals have precipitated which greatly increase in quantity when the reaction mixture is stirred up in water. The reaction product so obtained is S-aza- (linear naphthoxazole)-4,9-quinone. Following recrystallization from dimethylformamide, xylene, or nitrobenzene, yellow to orange crystals are obtained which darken when heated to about 280 C. and melt with decomposition at temperatures above 300 C.

Example II Approximately 10 grams of acetamido-7-chloro-5,8- quinolinequinone is heated to boiling with 100 cubic centimeters of nitrobenzene until the evolution of hydrochloric acid subsides. The nitrobenzene is now driven off by means of steam, and the dark residue is filtered oil by vacuum. It is then recrystallized from dimethylformarnide. The properties of the resultant 2-methyl-8- aza-(linear naphthoxazole)-4,9-quinone agree with those of the material obtained in the preceding example.

Example Ill About 23 grams of 6,7-dichloro-5,8-quinoliuequinone is mixed with 21 grams of sodium nitrite and introduced into a warm mixture of 100 cubic centimeters of water and 200 cubic centimeters of dimethylformamide. The temperature is maintained at 80 C. for 20 minutes, and the batch is then mixed with activated carbon and vacuum filtered. When the filtrate has been kept at C. for 1 hour, the sodium salt of 6-nitro-7-hydroxy- 5,8-quinolinequinone is isolated in the form of orangecolored crystals which decompose, after first sintering, at 230 C.240 C.

About 8 grams of the sodium salt of 6-nitro-7-hydroxy-S,S-quinolinequinone is suspended in 80 cubic centimeters of alcohol and reduced by addition of 28 grams of sodium dithionite in 280 cubic centimeters of water at temperatures above 50 C. The material precipitating on cooling is filtered off by vacuum, dried, and then re-' crystallized from an alcohol-water mixture with addition of activated carbon. The brown, microcrystalline substance obtained, which darkens and decomposes when heated at 210220 C., is 6-amino-7-hydroxy-5,8-quinolinequinone. It completely dissolves, with indigo-blue color, in soda solution.

Example IV Approximately 25 grams of the 6-amino-7-hydroxy- 5,8-quinolinequinone prepared as above is heated to the boil for 3 hours in 150 cubic centimeters of benzoyl chloride and 0.5 cubic centimeter of concentrated sulfuric acid. Following decomposition of the excess benzoyl chloride by means of aqueous alkali, 7.5 grams of 2 phenyl-8-aza-(linear naphthoxazole)-4,9-quinone is obtained. This is purified by recrystallization from dimethylformarnide, forming a yellow, crystalline substance which melts with decomposition at 276 C.

Example V About 15 grams of 6-amino-7-hydroxy-5,8-quinoline-, quinone is heated to the boil for 2 hours in a mixture of 70 cubic centimeters acetic anhydride, 200 cubic centi, meters xylene, and 0.5 cubic centimeter concentrated sulfuric acid. Concentration of the reaction mixtures to one-fifth its initial volume yields 5 grams of yellowish crystals the properties of which, following recrystalliza-. tion from dimethylformamide, are the same as those of 2-methyl-8-aza-(linear naphthoxazole)-4,9-quinone obtained as described in Examples I and II.

Example VI About 22 grams of 6-amino-7-chloro-5,8-quinolinequinone and 25 grams of crystalline sodium sulfide are dissolved in cubic centimeters of water. After 20 minutes 12 grams of benzldehyde is added, and the mixture is acidified 5 minutes later by dropwise addition of 10 cubic centimeters of glacial acetic acid. This is followed by 1 hour of boiling. After cooling, yellowishbrown crystals are filtered off which are reduced by means of 40 grams sodium hydroxide and 40 grams sodium dithionite in 1800 milliliters of water, filtered, and reprecipitated with air. 2-phenyl-8-aza-(linear naphthothiazole) -4,9-quinone is obtained in the form of a greenish-yellow powder which turns yellow-orange and melts at 274 C. on recrystallization from xylene.

Example VII 6-amino-7-chloro-S,8-quinolinequiuone is reacted with sodium sulfide in accordance with the procedure in Example 6 except that 16.5 grams of o-vanillin'is used for the condensation instead of the benzaldehyde. Following reduction of the vacuum-filtered product by means of sodium dithionite and re-oxidation with air, the product is dried and then recrystallized from o-dichlorobenzene, yielding 2-(2-hydroxy 3 methoxyphenyl)-8-aza-(linear naphthothiazole)-4,9-quinone in the form of small orangecolored crystals that melt at 300-301 C.

Example VIII 6-arnino-7-chloro-5,8-quinolinequinone is reacted with sodium sulfide as described in Example VI, but 17.7 grams of p-diethylaminobenzaldehyde is used instead of benzaldehyde. Following purification of the reaction prod net as described in Example VII, 2-(4-N,N-diethylaminophenyl)-aza-(linear naphthothiazole)-4,9-quinone is obtainedintheform of intensely blue-violet crystals that melt at 275 C. r

. Example IX -=6-amino-7-chloro-5,8-quinolinequinone is reacted with sodium sulfide inv a manner analogous to that of Example- 6, but the benzaldehyde is replaced by 13 grams of benza1dehyde-4-su1fonic acid. Following reduction of the reaction product by means of sodium dithionite and reoxidation with air, the product is acidified with dilute sulfuric acid. Recrystallization from water then. yields the. sodium salt of 2-(4-sulfonylphenyl)-8-aza:,(linea1'.:;

naphthothiazole) -4,9-quinone. This substance decomposes when heated above 300 C.

Example X 6-amino-7-ohloro-5,S-quinolinequinone is reacted with sodium sulfied in the manner described in Example VI, 11.5 grams of pyridine-4-aldehyde being used in lieu of the benzaldehyde. Following reduction with sodium dithionite, re-oxidation with air, and drying, the product is reprecipitated from 1,2,4-trichlorober1zene. The small yellow crystals resulting are 2-(4-pyn'dyl)-8-aza-(linear naphthothiazole)-4,9-quinone, melting at 349 C.

Having thus described the subject matter of our invention, what it is desired to secure by Letters Patent of the United States is:

1. A compound selected from the group consisting of compounds represented by the following formula:

wherein R is selected from the group consisting of phenyl, 2-hydroxy-3-methoxyphenyl, 4-N,N-diethyl-aminophenyl, 4-sulfonyl-phenyl, Z-furyl and 4-pyridyl.

2. 2-Phenyl-8-aza-(linear naphthothiazole) 4,9 quinone.

3. 2 (2 Hydroxy 3 methoxyphenyl) 8 aza- (linear naphthothiazole)4,9 quinone.

4. 2 (4 N,N diethylarninophenyl) aza (linear naphthothiazole)-4,9-quinone.

5. 2 (4 Sulfonylphenyl) 8 aza (linear naphthothiazole) -4,9-quinone.

6. 2-(2-Furyl)-8-aza-*(linear naphthothiaZ0le)-4,9-qui none.

7. 2(4-Pyridyl)-8-aza-(linear quinone.

naphthothiazole) 4,9-

No references cited. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS REPRESENTED BY THE FOLLOWING FORMULA:
 4. I - (4 - N,N - DIETHYLAMINOPHENYL) - AZA - (LINEAR NAPHTHOTHIAZOLE)-4,9-QUINONE. 